Medicine and Health Sciences Commons^™

Γ-Secretase Inhibitor Alleviates Acute Airway Inflammation Of Allergic Asthma In Mice By Downregulating Th17 Cell Differentiation, Weixi Zhang, Xueya Zhang, Anqun Sheng, Cuiye Weng, Tingting Zhu, Wei Zhao, Changchong Li

Pediatrics Publications

T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. Th17 cell differentiation requires Notch signaling. γ-Secretase inhibitor (GSI) blocks Notch signaling; thus, it may be considered as a potential treatment for allergic asthma. The aim of this study was to evaluate the effect of GSI on Th17 cell differentiation in a mouse model of allergic asthma. OVA was used to induce mouse asthma model in the presence and absence of GSI. GSI ameliorated the development of OVA-induced asthma, including suppressing airway inflammation responses and reducing the severity of clinical signs. GSI also significantly …

Chemokine Function In Periodontal Disease And Oral Cavity Cancer, Sinem Esra Sahingur, W. Andrew Yeudall

Periodontics Publications

The chemotactic cytokines, or chemokines, comprise a superfamily of polypeptides with a wide range of activities that include recruitment of immune cells to sites of infection and inflammation, as well as stimulation of cell proliferation. As such, they function as antimicrobial molecules and play a central role in host defenses against pathogen challenge. However, their ability to recruit leukocytes and potentiate or prolong the inflammatory response may have profound implications for the progression of oral diseases such as chronic periodontitis, where tissue destruction may be widespread. Moreover, it is increasingly recognized that chronic inflammation is a key component of tumor …

Critical Appraisal Of Dabigatran In The Treatment Of Deep Vein Thrombosis And Pulmonary Embolism, Kelechi C. Ogbonna, Dave L. Dixon

Pharmacotherapy and Outcomes Science Publications

Objective

To compare the safety and efficacy of dabigatran to warfarin for the treatment of deep vein thrombosis and pulmonary embolism.

Background

Venous thromboembolism (VTE) is a disease comprised of two conditions: deep vein thrombosis and pulmonary embolism. VTE is a major cause of morbidity and mortality worldwide with an annual incidence estimated at 1–3 cases per 1,000 individuals. This incidence increases with age from 0.1 per 1,000 in adolescence to eight per 1,000 in those 80 years of age and older. As the proportion of patients 65 years of age and older expands, the number of patients presenting with …

A Simple Method For Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation Of Key Principles From Heparin/Heparan Sulfate-Binding Proteins, Aurijit Sarkar, Umesh R. Desai

Medicinal Chemistry Publications

Glycosaminoglycans (GAGs) affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS) on proteins that in turn helps predict high specific GAG–protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an …

Liver X Receptor-Dependent Inhibition Of Microglial Nitric Oxide Synthase 2, Julie R Secor Mcvoy, Hanadi Ajam Oughli, Unsong Oh

Neurology Publications

Background

The nuclear receptor liver X receptor (LXR) exerts transcriptional control over lipid metabolism and inflammatory response in cells of the myeloid lineage, suggesting that LXR may be a potential target in a number of chronic neuroinflammatory and neurodegenerative diseases where persistent microglial activation has been implicated in the pathogenesis.

Methods

The effect of LXR activation on microglia and central nervous system (CNS) inflammation was studied using a synthetic LXR agonist in cultured microglia, a microglial cell line and experimental allergic encephalomyelitis (EAE), an animal model of CNS inflammation.

Results

LXR activation inhibited nitric oxide synthase 2, inducible (Nos2 …

Virginia Dental Journal (Vol. 92, No. 1, 2015)

Virginia Dental Journal

No abstract provided.

Missed Opportunities For The Diagnosis Of Colorectal Cancer, Laura A. Siminoff, Heather L. Rogers, Sonja Harris-Haywood

Biochemistry and Molecular Biology Publications

Objective. To examine patient and medical characteristics which predict a missed diagnostic opportunity (MDO) for colorectal cancer (CRC). Methods. The sample consisted of 252 patients diagnosed with Stages 1–4 CRC who were diagnosed in the prior six months, had experienced symptoms prior to diagnosis, and were not diagnosed through routine screening. Systematic review of all medical records prior to patients’ diagnosis was conducted. An MDO was defined as a clinical encounter where, even in the presence of presumptive CRC symptoms, the CRC diagnostic process is not started. Results. 92 patients (36.5%) experienced an MDO. Almost 80% of alternate diagnoses were …

Interrogating The Venom Of The Viperid Snake Sistrurus Catenatus Edwardsii By A Combined Approach Of Electrospray And Maldi Mass Spectrometry, Alex Chapeaurouge, Md Abu Reza, Stephen P. Mackessy, Paulo C. Carvalho, Richard H. Valente, André Teixeira-Ferreira, Jonas Perales, Qingsong Lin, R. Manjunatha Kini

Biochemistry and Molecular Biology Publications

The complete sequence characterization of snake venom proteins by mass spectrometry is rather challenging due to the presence of multiple isoforms from different protein families. In the present study, we investigated the tryptic digest of the venom of the viperid snake Sistrurus catenatus edwardsii by a combined approach of liquid chromatography coupled to either electrospray (online) or MALDI (offline) mass spectrometry. These different ionization techniques proved to be complementary allowing the identification a great variety of isoforms of diverse snake venom protein families, as evidenced by the detection of the corresponding unique peptides. For example, ten out of eleven predicted …

Progressive Cognitive Deficit, Motor Impairment And Striatal Pathology In A Transgenic Huntington Disease Monkey Model From Infancy To Adulthood, Anthony W. S. Chan, Jie Jiang, Yiju Chen, Chunxia Li, Melinda S. Prucha, Yijuan Hu, Tim Chi, Sean Moran, Tayeb Rahim, Shihua Li, Xiaojiang Li, Stuart M. Zola, Claudia M. Testa, Hui Mao, Rosa Villalba, Yoland Smith, Xiaodong Zhang, Jocelyne Bachevalier

Neurology Publications

One of the roadblocks to developing effective therapeutics for Huntington disease (HD) is the lack of animal models that develop progressive clinical traits comparable to those seen in patients. Here we report a longitudinal study that encompasses cognitive and motor assessment, and neuroimaging of a group of transgenic HD and control monkeys from infancy to adulthood. Along with progressive cognitive and motor impairment, neuroimaging revealed a progressive reduction in striatal volume. Magnetic resonance spectroscopy at 48 months of age revealed a decrease of N-acetylaspartate (NAA), further suggesting neuronal damage/loss in the striatum. Postmortem neuropathological analyses revealed significant neuronal loss in …

Virginia Dental Journal (Vol. 92, No. 4, 2015)

Virginia Dental Journal

No abstract provided.

We Happy Few: Accomplishments In Calendar 2014, Edward F. Ansello

Director's Editorials from Age in Action

The Virginia Center on Aging recognizes strides its staff has made in confronting elder abuse and domestic violence in later life; building and improving lifelong learning opportunities across the Commonwealth for mid-life and older adults; delivering interprofessional geriatrics training for health care providers and measuring the impacts of this training upon the patients they care for; training clinical students to partner across professions to improve geriatrics care; developing and delivering education and training programs to audiences in state, regional, and national conferences and webinars on topics ranging from gerontological education to aging with lifelong disabilities, community health to interdisciplinary teamwork; …

Culture-Centered Approaches: The Relevance Of Assessing Emotional Health For Latinos With Type 2 Diabetes, Jeannie Belinda Concha, Brianna Mezuk, Bonnie Duran

Family Medicine and Population Health Publications

Objective

Within Latino culture, there is a belief that strong emotions can cause diabetes. Because of this belief and evidence regarding the bi-directional relationship between depression and diabetes, the objectives of this study were to determine if medical doctors are asking Latinos with diabetes about emotional problems and to assess attitudes toward professional help for emotional problems.

Research design and methods

Data come from the nationally representative National Latino and Asian American Study and the National Comorbidity Survey Replication study. Only Latino subsamples were included (n=3076). A smaller subsample with complete data (n=2568) was used for the inquiry outcome variable. …

Comparison Of Effectiveness Of Cefovecin, Doxycycline, And Amoxicillin For The Treatment Of Experimentally Induced Early Lyme Borreliosis In Dogs, Bettina Wagner, John Johnson, David Garcia-Tapia, Nicole Honsberger, Vickie King, Catherine Strietzel, John M. Hardham, Thomas J. Heinz, Richard T. Marconi, Patrick F.M. Meeus

Microbiology and Immunology Publications

Background

While Koch’s postulates have been fulfilled for Lyme disease; causing transient fever, anorexia and arthritis in young dogs; treatment of sero-positive dogs, especially asymptomatic animals, remains a topic of debate. To complicate this matter the currently recommended antibiotic treatments of Lyme Disease in dogs caused by Borrelia burgdorferi require daily oral administrations for 31 days or longer, which makes non-compliance a concern. Additionally, there is no approved veterinary antimicrobial for the treatment of Lyme Disease in dogs in the USA and few recommended treatments have been robustly tested.

In vitro testing of cefovecin, a novel extended-spectrum cephalosporin, demonstrated inhibition …

Identification Of Small-Molecule Inhibitors Against Meso-2, 6-Diaminopimelate Dehydrogenase From Porphyromonas Gingivalis, Victoria N. Stone, Hardik I. Parikh, Fadi El-Rami, Xiuchun Ge, Weihau Chen, Yan Zhang, Glen E. Kellogg, Ping Xu

Microbiology and Immunology Publications

Species-specific antimicrobial therapy has the potential to combat the increasing threat of antibiotic resistance and alteration of the human microbiome. We therefore set out to demonstrate the beginning of a pathogen-selective drug discovery method using the periodontal pathogen Porphyromonas gingivalis as a model. Through our knowledge of metabolic networks and essential genes we identified a “druggable” essential target, meso-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a highthroughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivalis was first expressed and purified in …

Redox Regulation Of Nlrp3 Inflammasomes: Ros As Trigger Or Effector?, Justine M. Abais, Min Xia, Yang Zhang, Krishna M. Boini, Pin-Lan Li

Pharmacology and Toxicology Publications

Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most …

Use Of Prescription Drugs And Future Delinquency Among Adolescent Offenders, Tess K. Drazdowski, Lena Jäggi, Alicia Borre, Wendy L. Kliewer

Psychology Publications

Non-medical use of prescription drugs (NMUPD) by adolescents is a significant public health concern. The present study investigated the profile of NMUPD in 1349 adolescent offenders from the Pathways to Desistance project, and whether NMUPD predicted future delinquency using longitudinal data. Results indicated that increased frequency and recency of NMUPD in adolescent offenders are related to some demographic factors, as well as increased risk for violence exposure, mental health diagnoses, other drug use, and previous delinquency, suggesting that severity of NMUPD is important to consider. However, ANCOVA analyses found that NMUPD was not a significant predictor of drug-related, non-aggressive, or …

Integrating Mrna And Mirna Weighted Gene Co-Expression Networks With Eqtls In The Nucleus Accumbens Of Subjects With Alcohol Dependence, Mohammed Mamdani, Vernell Williamson, Gowon O. Mcmichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D. Van Der Vaart, Bradley Todd Webb, Silviu-Alin Bacanu, Gursharan Kalsi, Coga Consortium, Kenneth S. Kendler, Michael F. Miles, Danielle Dick, Brien P. Riley, Catherine Dumur, Vladimir I. Vladimirov

Psychology Publications

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and …

Developmental Changes In Genetic And Shared Environmental Contributions To Smoking Initiation And Subsequent Smoking Quantity In Adolescence And Young Adulthood, Cristina B. Bares, Kenneth S. Kendler, Hermine H. Maes

Psychiatry Publications

Background

Few studies examining the genetic architecture of cigarette smoking have focused on adolescents or examined developmental changes in additive genetic, shared environment and unique environmental influences on liability to initiate cigarette smoking and quantity of cigarettes smoked. The aim of this study is to add to the literature on liability to initiate and use cigarettes during adolescence using a nationally representative sample.

Method

Data for this study came from adolescent and young adult twin pairs (ages 14-33) from the National Longitudinal Study of Adolescent to Adult Health. We ran a series of developmental causal-contingent-common pathway models to examine whether …

Genetic Network Properties Of The Human Cortex Based On Regional Thickness And Surface Area Measures, Anna R. Docherty, Chelsea K. Sawyers, Matthew S. Panizzon, Michael C. Neale, Lisa T. Eyler, Christine Fennema-Notestine, Carol E. Franz, Chi-Hua Chen, Linda K. Mcevoy, Brad Verhulst, Ming T. Tsuang, William S. Kremen

Psychiatry Publications

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques—biometrical genetic modeling, cluster analysis, and graph theory—to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several …

Political Attitudes Develop Independently Of Personality Traits, Peter K. Hatemi, Brad Verhulst

Psychiatry Publications

The primary assumption within the recent personality and political orientations literature is that personality traits cause people to develop political attitudes. In contrast, research relying on traditional psychological and developmental theories suggests the relationship between most personality dimensions and political orientations are either not significant or weak. Research from behavioral genetics suggests the covariance between personality and political preferences is not causal, but due to a common, latent genetic factor that mutually influences both. The contradictory assumptions and findings from these research streams have yet to be resolved. This is in part due to the reliance on cross-sectional data and …

Genome-Wide Association Data Suggest Abcb1 And Immune-Related Gene Sets May Be Involved In Adult Antisocial Behavior, J E. Salvatore, A C. Edwards, J N. Mcclintick, T B. Bidgeli, A Adkins, F Aliev, H J. Edenberg, T Foround, V Hesselbrock, J Kramer, J I. Nurnberger, M Schuckit, J A. Tischfield, X Xuei, D Dick

Psychiatry Publications

Adult antisocial behavior (AAB) is moderately heritable, relatively common and has adverse consequences for individuals and society. We examined the molecular genetic basis of AAB in 1379 participants from a case–control study in which the cases met criteria for alcohol dependence. We also examined whether genes of interest were expressed in human brain. AAB was measured using a count of the number of Antisocial Personality Disorder criteria endorsed under criterion A from the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). Participants were genotyped on the Illumina Human 1M BeadChip. In total, all single-nucleotide polymorphisms (SNPs) accounted for …

Who Are Those “Risk-Taking Adolescents”? Individual Differences In Developmental Neuroimaging Research, James M. Bjork, Dustin A. Pardini

Psychiatry Publications

Functional magnetic resonance imaging (fMRI) has illuminated the development of human brain function. Some of this work in typically-developing youth has ostensibly captured neural underpinnings of adolescent behavior which is characterized by risk-seeking propensity, according to psychometric questionnaires and a wealth of anecdote. Notably, cross-sectional comparisons have revealed age-dependent differences between adolescents and other age groups in regional brain responsiveness to prospective or experienced rewards (usually greater in adolescents) or penalties (usually diminished in adolescents). These differences have been interpreted as reflecting an imbalance between motivational drive and behavioral control mechanisms, especially in mid-adolescence, thus promoting greater risk-taking. While intriguing, …

Respiratory Motion Variability Of Primary Tumors And Lymph Nodes During Radiotherapy Of Locally Advanced Non-Small-Cell Lung Cancers, Nuzhat Jan, Geoffrey D. Hugo, Nitai Mukhopadhyay, Elisabeth Weiss

Radiation Oncology Publications

Background and purpose

The need for target adjustment due to respiratory motion variation and the value of carina as a motion surrogate is evaluated for locally advanced non-small-cell lung cancer.

Material and methods

Using weekly 4D CTs (with audio-visual biofeedback) of 12 patients, respiratory motion variation of primary tumors (PT), lymph nodes (LN) and carina (C) were determined.

Results

Mean (SD) 3D respiratory motion ranges of PT, LN and C were 4 (3), 5 (3) and 5 (3) mm. PT and LN (p = 0.003), and LN and C motion range were correlated (p = 0.03). Only 20 …

Spag17 Deficiency Results In Skeletal Malformations And Bone Abnormalities, Maria Eugenia Teves, Gobalakrishnan Sundaresan, David J. Cohen, Sharon L. Hyzy, Illya Kajan, Melissa Maczis, Zhibing Zhang, Richard M. Costanzo, Jamal Zweit, Zvi Schwartz, Barbara` D. Boyan, Jerome F. Strauss Iii

Obstetrics and Gynecology Publications

Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area …

Sperm Associated Antigen 6 (Spag6) Regulates Fibroblast Cell Growth, Morphology, Migration And Ciliogenesis, Wei Li, Abir Mukherjee, Jinhua Wu, Ling Zhang, Maria E. Teves, Hongfei Li, Shanti Nambiar, Scott C. Henderson, Alan R. Horwitz, Jerome F. Strauss Iii, Xianjun Fang, Zhibing Zhang

Obstetrics and Gynecology Publications

Mammalian Spag6 is the orthologue of Chlamydomonas PF16, which encodes a protein localized in the axoneme central apparatus, and regulates flagella/cilia motility. Most Spag6-deficient mice are smaller in size than their littermates. Because SPAG6 decorates microtubules, we hypothesized that SPAG6 has other roles related to microtubule function besides regulating flagellar/cilia motility. Mouse embryonic fibroblasts (MEFs) were isolated from Spag6-deficient and wild-type embryos for these studies. Both primary and immortalizedSpag6-deficient MEFs proliferated at a much slower rate than the wild-type MEFs, and they had a larger surface area. Re-expression of SPAG6 in the Spag6-deficient MEFs …

Screening And Surveillance Ct Abdomen/Pelvis For Metastases In Patients With Soft-Tissue Sarcoma Of The Extremity, M. J. Thompson, J. Ross, G. Domson, W. Foster

Orthopaedic Surgery Publications

Objectives The clinical utility of routine cross sectional imaging of the abdomen and pelvis in the screening and surveillance of patients with primary soft-tissue sarcoma of the extremities for metastatic disease is controversial, based on its questionable yield paired with concerns regarding the risks of radiation exposure, cost, and morbidity resulting from false positive findings.

Methods Through retrospective review of 140 patients of all ages (mean 53 years; 2 to 88) diagnosed with soft-tissue sarcoma of the extremity with a mean follow-up of 33 months (0 to 291), we sought to determine the overall incidence of isolated abdominopelvic metastases, their …

Quality Control Material For The Detection Of Somatic Mutations In Fixed Clinical Specimens By Next-Generation Sequencing, Catherine I. Dumur, Jorge A. Almenara, Celeste N. Powers, Andrea Ferreira-Gonzalez

Pathology Publications

Background

Targeted next generation sequencing (NGS) technology to assess the mutational status of multiple genes on formalin-fixed, paraffin embedded (FFPE) tumors is rapidly being adopted in clinical settings, where quality control (QC) practices are required. Establishing reliable FFPE QC materials for NGS can be challenging and/or expensive. Here, we established a reliable and cost-effective FFPE QC material for routine utilization in the Ion AmpliSeq™ Cancer Hotspot Panel v2 (CHP2) assay.

Methods

The performance characteristics of the CHP2 assay were determined by sequencing various cell line mixtures and 55 different FFPE tumors on the Ion Torrent PGM platform. A FFPE QC …

Waterpipe Smoking And Regulation In The United States: A Comprehensive Review Of The Literature, Linda Haddad, Omar El-Shahawy, Roula Ghadban, Tracey E. Barnett, Emily Johnson

Social and Behavioral Sciences Publications

Background: Researchers in tobacco control are concerned about the increasing prevalence of waterpipe smoking in the United States, which may pose similar risks as cigarette smoking. This review explores the prevalence of waterpipe smoking in the United States as well as the shortcomings of current U.S. policy for waterpipe control and regulation. Methods: Researchers conducted a literature review for waterpipe articles dated between 2004 and 2015 using five online databases: MEDLINE, CINHAHL, ScienceDirect, PMC, and Cochrane Library. Results: To date, few studies have explored the marketing and regulation of waterpipe smoking in the U.S., which has increased …

Upward Communication About Cancer Screening—Adolescent Daughter To Mother, Maghboeba Mosavel, Katie A. Ports

Social and Behavioral Sciences Publications

Substantial breast and cervical cancer disparities exist in the United States, particularly among African American women with low social economic status. There is considerable potential for discussions about cancer prevention between mothers and daughters. However, upward communication, from child to parent, remains a relatively novel research area, and it remains unclear how receptive mothers would be to messages from their daughter about cancer, a topic that may be considered culturally inappropriate for daughters to initiate. In this study, we simulated cancer message delivery to daughters and then conducted direct observation of daughters as they recalled and shared the message with …

Detrimental Effects Of Duplicate Reads And Low Complexity Regions On Rna- And Chip-Seq Data, Mikhail G. Dozmorov, Indra Adrianto, Cory B. Giles, Edmund Glass, Stuart B. Glenn, Courtney Montgomery, Kathy L. Sivils, Lorin E. Olson, Tomoaki Iwayama, Willard M. Freeman, Christopher J. Lessard, Jonathan D. Wren

Biostatistics Publications

Background

Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments.

Methods

We assessed the effect of data processing steps on the alignment statistics and the functional enrichment analysis results of RNA- and ChIP-seq data. We compared …